Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics
Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics
复制标题
DOI：
10.1016/j.nbd.2017.01.001
复制
发表时间：
2017-04-01
影响因子：
6.1
通讯作者：
Hughes, Stephanie M.
中科院分区：
文献类型：
--
作者：
Best, Hannah L.;Neverman, Nicole J.;Hughes, Stephanie M.
Batten病（神经元蜡样质脂褐质沉积症）是指一组主要影响儿童的神经退行性溶酶体贮积病。目前还没有有效的治疗方法，许多相关基因产物的功能也是未知的。在这里，我们将胎儿神经培养物从两种遗传上不同的羊形式的巴滕病，突变的溶酶体蛋白编码基因CLN5和内质网膜蛋白编码基因CLN6，分别。我们发现，与未受影响的细胞相比，这两种形式的自噬、酸性细胞器和突触回收都出现了类似的减少。然后，我们开发了一种高通量筛选，并测试了在CLN6缺陷神经培养物中用慢病毒介导的CLN5或CLN6基因转移和贝特类药物吉非贝齐和非诺贝特校正缺陷细胞。这些分析提供了一个简单的系统，在体内测试之前快速筛选候选疗法或药物库。(C)2017爱思唯尔公司All rights reserved.
Batten disease (neuronal ceroid lipofuscinosis) refers to a group of neurodegenerative lysosomal storage diseases predominantly affecting children. There are currently no effective treatments, and the functions of many of the associated gene products are unknown. Here we characterise fetal neural cultures from two genetically distinct sheep forms of Batten disease, with mutations in the lysosomal protein encoding gene CLN5 and endoplasmic reticulum membrane protein encoding gene CLN6, respectively. We found similar reductions in autophagy, acidic organelles and synaptic recycling in both forms compared to unaffected cells. We then developed a high throughput screen and tested for correction of deficient cells with lentiviral-mediated CLN5 or CLN6 gene transfer and fibrate drugs, gemfibrozil and fenofibrate in CLN6 deficient neural cultures. These assays provide a simple system to rapidly screen candidate therapies or libraries of drugs prior to in vivo testing. (C) 2017 Elsevier Inc. All rights reserved.